NM_000051.4:c.9139C>T

ATM · NP_000042.3:p.(Arg3047Ter) · NM_000051.4

GRCh37: chr11:108236203 C>T · GRCh38: chr11:108365476 C>T

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PVS1 very strong PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Arg3047Ter)

gnomAD AF

1.61091656195709e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000051.4:c.9139C>T (p.Arg3047Ter) is a nonsense variant in exon 63 of ATM, creating a premature termination codon at the most C-terminal residue considered pathogenic by the HBOP VCEP (p.Arg3047). PVS1 is applied at very strong strength under the ATM PVS1 Decision Tree as a null variant in a gene where loss of function is a known disease mechanism.

This variant has been reported in ClinVar as Pathogenic by the ClinGen HBOP VCEP expert panel and by 18 clinical laboratories (ClinVar Variation ID: 3029).

The variant is present in gnomAD v4.1 at an extremely low frequency (AF=1.61×10⁻⁵, 26/1,613,988 alleles; no homozygotes), consistent with a rare disease-causing variant. It is also present in gnomAD v2.1 at similar frequency (AF=1.77×10⁻⁵, 5/282,840 alleles).

Functional characterization by Guo et al. (2010, PMID 21150274) demonstrates that the R3047X mutant protein is expressed but specifically deficient in oxidation-dependent ATM activation while retaining MRN/DNA-dependent activation. Cells from an A-T patient with this variant showed moderate radiosensitivity, consistent with preserved DNA damage response but lost oxidative stress signaling.

Chessa et al. (2009, PMID 19691550) identified c.9139C>T in two Italian A-T families from Central Italy, confirming observation of this variant in individuals with classical ataxia-telangiectasia.

No VCEP-approved functional assay data, case-control studies, or detailed co-segregation data were available from the reviewed sources. Additional supporting evidence may exist in curated databases not accessible in this assessment. The ClinGen expert panel classification of Pathogenic likely incorporates proband data and/or additional supporting criteria not available here.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.5.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	NM_000051.4:c.9139C>T is a nonsense variant producing p.Arg3047Ter in ATM, a gene where loss of function is a well-established disease mechanism. The VCEP explicitly identifies p.Arg3047 as the most C-terminal residue considered pathogenic (PMIDs: 8755918, 19691550, 18560558, 10980530, 26628246). This null variant truncates the ATM protein within the FATC domain (exon 63, the terminal coding exon). Per the ATM PVS1 Decision Tree, PVS1 is applied at very strong strength.	vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment PMID:21150274 PMID:19691550
PS1	N/A	PS1 under the ATM VCEP is for missense changes at the same amino acid as a known pathogenic missense, or for splicing variants per the PS1 Splicing table. This variant is a nonsense substitution, not a missense change or a splicing variant.	cspec
PS2	N/A	VCEP declares PS2 not applicable: de novo occurrences have not been observed for ATM-related conditions and phase cannot be reliably determined for autosomal recessive disorders.	cspec
PS3	Not met	No variant-specific functional data from VCEP-approved assays (kinase activity assay per Mitui 2009/Barone 2009/Scott 2002, or radiosensitivity assay) are available for c.9139C>T. Functional data in PMID 21150274 (Guo et al. 2010) demonstrates loss of oxidative activation in purified R3047X ATM protein, but this assay is not among the VCEP-approved functional assays listed in the clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx.	cspec PMID:21150274
PS4	Not met	VCEP PS4 requires a case-control study with p≤0.05 AND (OR/HR/RR ≥2 OR lower 95% CI ≥1.5). No such case-control study was identified for c.9139C>T in the reviewed literature. Proband counting (PS4_Moderate) is not permitted under this VCEP.	cspec
PS5	N/A	PS5 is not recognized as a standalone criterion by the HBOP VCEP v1.5.0 for ATM. The original ACMG PS5 (same criterion as PS4 but at lower statistical threshold) is not included in the VCEP criteria set.	cspec
PM1	N/A	VCEP declares PM1 not applicable for ATM: benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined.	cspec
PM2	Not met	gnomAD v4.1 allele frequency is 1.61×10⁻⁵ (0.00161%, 26/1,613,988 alleles), which exceeds the VCEP PM2_Supporting threshold of ≤0.001% (≤1.0×10⁻⁵). The variant is present in gnomAD v2.1 at similar low frequency (1.77×10⁻⁵, 5/282,840 alleles). No homozygotes observed in either dataset.	gnomad_v4 gnomad_v2 cspec
PM5	N/A	The VCEP PM5 rule applies to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant creates a termination codon at exactly p.Arg3047 (the defined C-terminal boundary), not upstream of it. The variant itself — p.Arg3047Ter — is cited by the VCEP as the most C-terminal known pathogenic variant and defines the PM5 boundary rather than falling within its scope.	cspec pm5_candidates
PM6	N/A	VCEP declares PM6 not applicable: informative de novo occurrences have not been observed for ATM-related conditions and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not met	PMID 19691550 (Chessa et al. 2009) reports two A-T families carrying c.9139C>T originating from Central Italy, confirming the variant is observed in A-T patients. However, the paper does not provide specific co-segregation data (number of affected relatives, genotypes of family members) that would allow application of PP1 under the VCEP framework, which requires segregation in 1, 2, or ≥3 affected relatives for the AR condition.	PMID:19691550 cspec
PP2	N/A	VCEP declares PP2 not applicable: ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	PP3 under the ATM VCEP applies to missense variants with REVEL >0.7333 or to splicing variants with SpliceAI ≥0.2. This is a nonsense variant; REVEL is not applicable. SpliceAI max delta score is 0.15 (<0.2 threshold). The BayesDel score of 0.617 does not have a defined VCEP PP3 threshold.	spliceai bayesdel cspec
PP4	N/A	VCEP declares PP4 not applicable: for autosomal dominant, breast cancer has multiple genetic etiologies; for autosomal recessive, such evidence is built into the A-T PM3/BP2 table.	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	VCEP BA1 threshold is grpmax Filtering AF >0.5% in gnomAD v4. The observed grpmax FAF is 4.37×10⁻⁵ (0.00437%), far below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	VCEP BS1 threshold is grpmax Filtering AF >0.05% in gnomAD v4. The observed grpmax FAF is 4.37×10⁻⁵ (0.00437%), below the BS1 threshold.	gnomad_v4 cspec
BS2	N/A	VCEP declares BS2 not applicable: ATM has incomplete penetrance.	cspec
BS3	Not met	No variant-specific benign functional data from VCEP-approved assays are available. The VCEP BS3_Moderate requires rescue of both an ATM-specific feature AND radiosensitivity; BS3_Supporting requires rescue of either. The available functional data (PMID 21150274) shows loss of oxidative activation, not rescue of normal function.	cspec PMID:21150274
BS4	N/A	VCEP declares BS4 not applicable: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight, and biallelic unaffected patients can be considered under BP2 instead.	cspec
BP1	N/A	VCEP declares BP1 not applicable: missense pathogenic variants are known for ATM, so the premise that primarily truncating variants cause disease does not hold.	cspec
BP2	Not met	BP2 requires proband-level data (confirmed in trans with a pathogenic variant in unaffected individuals ≥18 years with no evidence of A-T) per the ATM PM3/BP2 table. No such proband data was available in the reviewed sources to calculate BP2 points.	cspec vcep_atm_pm3_bp2_1_5
BP4	Not met	BP4 under the ATM VCEP applies to missense variants with REVEL ≤0.249 or splicing variants with SpliceAI ≤0.1. This is a nonsense variant; REVEL is not applicable. SpliceAI max delta is 0.15 (>0.1 threshold), so the splicing-based BP4 is not met.	spliceai cspec
BP5	N/A	VCEP declares BP5 not applicable: cases with multiple pathogenic variants have been observed with no noticeable phenotype difference, and ATM has low penetrance, making co-occurrence of pathogenic variants uninformative.	cspec
BP6	N/A	VCEP declares BP6 not applicable: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP3	N/A	Variant is a substitution, not an in-frame deletion/insertion in a repetitive region.
PM3	N/A	SKIP — trivially not applicable; PM3 requires detection in trans with a pathogenic variant, which requires proband-level phase data not assessed here.
PM4	N/A	SKIP — trivially not applicable; variant is a substitution, not a protein-length-altering in-frame deletion/insertion or stop-loss.
BP7	N/A	BP7 applies to synonymous and deep intronic variants. This variant is a nonsense substitution (c.9139C>T, p.Arg3047Ter), not a synonymous or intronic change.	cspec

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